1. Field of the Invention
The present invention is directed to certain radiodense medicarnents and methods for treatment of human or animal tissue using such medicaments in combination with radiation therapy, wherein these radiodense medicaments serve as radiosensitizers in high energy phototherapy. The inventors of the present invention have found that such medicaments are useful for treatment of a variety of conditions affecting the skin and related organs, the mouth and digestive tract and related organs, the urinary and reproductive tracts and related organs, the respiratory tract and related organs, the circulatory system and related organs, the head and neck, the endocrine and lymphoreticular systems and related organs, various other tissues, such as connective tissues and various tissue surfaces exposed during surgery, as well as various tissues exhibiting microbial, viral, fungal or parasitic infection. These medicaments are in various formulations that may include liquid, semisolid, solid or aerosol delivery vehicles, and are suitable for intracorporeal administration via various conventional modes and routes, including intravenous injection (i.v.), intraperitoneal injection (i.p.), intramuscular injection (i.m.), intracranial injection (i.c.), intratumoral injection (i.t.), intraepithelial injection (i.e.), transcutaneous delivery (t.c.), and per oesophageal (p.o.) administration. Irradiation of tissues containing such medicaments with ionizing radiation produces adesirable therapeutic response, such as destruction of microbial infection, reduction or elimination of tissue irritation, reduction or elimination of hyperproliferative tissue, reduction or elimination of cancerous or precancerous tissue, reduction or elimination of surface or subsurface lipocytes or lipid deposits, and many other similar indications.
2. Description of the Related Art
Diseased tissue or tumors, such as those of cancer, are often treated using high energy, highly penetrating ionizing radiation (i.e., ionizing radiation, or radiation), in a process known as radiation therapy.
Conventional radiation therapy (which typically uses ionizing radiation with energies of 1 keV or higher) generally works by attacking rapidly growing cells with ionizing radiation. Use of such radiation is attractive due to its ability to penetrate deeply into tissue, especially when diseased tissue consists of, or is located within, bone or other dense or opaque structures. Unfortunately, using rapid growth as the sole targeting criterion does not limit the effects of such treatment to diseased tissue, and as a result, heathy tissue is often destroyed or damaged.
As a result, some improvements have been made in the methods for delivery of the radiation to the disease site so as to limit the effects of such radiation to the general area of the diseased tissue. However, since healthy tissue and diseased tissue typically have a similar biological response to ionizing radiation, a need exists to improve the potency of (or biological response to) the delivered radiation within the vicinity of the diseased tissue to the diseased tissue, so as to not affect the surrounding healthy tissue.
Accordingly, some investigators have focused their efforts on developing agents that become activated by, or increase the therapeutic potential of, such ionizing radiation. Such agents are known as radiosensitizers, and when used in combination with ionizing radiation constitute a therapeutic modality known as high energy phototherapy. Since radiosensitizers function by absorbing or otherwise interacting with penetrating, ionizing radiation and locally transforming this radiation into a more biologically active form, it is desirable that such radiosensitizer agents exhibit high intrinsic radiodensity and a capacity for preferential concentration in diseased tissue (thus allowing maximal, selective delivery of the therapeutic effects of such radiation to such diseased tissue containing such agent).
Due to the focal nature of many diseases, it is desirable to achieve this preferential concentration of the radiosensitizer through natural processes or via localized application of agent. The desired result is then for radiation to become more efficacious when the radiosensitizer is present in tissue, so that less radiation is needed to treat the lesion, tumor or other diseased tissue, and accordingly, potential damage to surrounding healthy tissue, resulting from collateral exposure to the radiation, is reduced. Hence, safety and efficacy can be improved by having agents capable of preferential concentration in diseased tissue.
The ultimate success or failure of high energy phototherapy thus depends on: (1) therapeutic performance of radiosensitizer agents, and (2) disease specificity in delivery of agents to the site of disease or diseased tissue. Currently used agents and targeting approaches, however, have had unacceptable results in each of these categories.
The therapeutic performance of a radiosensitizer is a function of enhanced absorption of the applied radiation dose in sensitized tissues relative to that in non-sensitized tissues. This differential absorption is commonly effected by use of radiodense agents having a high absorption cross-section for a particular type of radiation (such as x-rays). For example, metal or halogen atoms are often used, either in atomic form or incorporated into a molecular carrier, due to their high x-ray cross-section. Absorption of x-rays by such radiodense materials appears to lead to secondary radiative emissions, ionization, and other chemical or physical processes that increase the localized cytotoxicity of the applied energy (i.e., radiation-induced cell death, or “light cytotoxicity”).
However, a high light cytotoxicity is not enough to make an agent an acceptable agent. The agent must also have a negligible effect when energy is not applied (i.e., have a low toxicity in the absence of radiation, or “dark cytotoxicity”). Unfortunately, many agents presently under investigation as radiosensitizers are disadvantageous as they either have (a) a relatively high dark cytotoxicity or (b) a low light (cytotoxicity)-to-dark cytotoxicity ratio which limits their effectiveness and acceptability. In contrast, agents having a high light-to-dark cytotoxicity ratio are desirable because they (1) can be safely used over a range of dosages, (2) will exhibit improved efficacy at the treatment site (due to the compatibility with use at higher dosages as a consequence of their relative safety), and (3) will be better tolerated throughout the patient's body.
An additional problem with many current radiosensitizers is that the agent does not achieve significant preferential concentration in diseased tissue. Specifically, most radiosensitizer targeting has been based on physical targeting, such as diffusion into tumors through leaky neovasculature, which ultimately succeeds or fails based on permeability of the tumor to agents that are aqueously soluble or are in a suspension formulation. As a result, large doses of the agent typically need to be administered, either locally or systemically, so as to saturate all tissues, hopefully reaching a therapeutic level in the desired treatment region or target. After such agent administration, a patient has to wait a clearance time of from hours to days to allow excess agent to hopefully clear from the healthy tissues surrounding the desired treatment site. Thereafter, irradiation of residual agent at the treatment site hopefully produces the desired therapeutic effect in the diseased tissue. This approach unfortunately can also damage healthy surrounding tissue by undesired activation of residual agent still present in the healthy surrounding tissue. One approach to solving this problem is to couple the radiosensitizer with a moiety capable of providing improved biotargetting of the diseased tissue. This, however, has proven to be very difficult to achieve.
It would also be highly desirable if the radiosensitizer could be used to improve identification of target size, location and depth so that the therapeutic radiation could be more precisely delivered to the target, such as to a cancerous tumor. Further, combined diagnostic use (as a contrast agent) and therapeutic use (as a radiosensitizer) of the agent would reduce risk to the patient by (1) reducing the number of required procedures necessary for diagnosis and treatment, (2) reducing the overall diagnosis and treatment time, and (3) reducing cost.
Thus, the inherent disadvantages of various current radiosensitizer agents and medicaments containing such agents have made acceptable radiation therapy for various human and animal conditions difficult or impossible.
Therefore, it is an object of the present invention to provide new intracorporeal radiodense medicaments, medical uses for such medicaments based on improved specificity of such medicaments for the desired tissue to be treated, and methods for treatment using such medicaments, thereby resulting in increased efficacy and safety and reduced cost of treatment.